Chronic pancreatitis is a devastating consequence of alcohol abuse. Despite extensive experimental work, the pathophysiology of ethanol-induced pancreatitis remains unclear. The discovery that extracellular proteolysis associated with the plasminogen (plg) system participates in tissue remodeling has led to increased recognition of the key role of this system in tissue repair in several organs. However, the role of the plg system in ethanol-induced pancreas damage remains unexplored. The broad, long-term objective of this proposal is to elucidate the participation of the plg system in the development of pancreatic fibrosis induced by ethanol. Preliminary data using mice genetically deficient in plg demonstrated that plasmin activity is required for pancreas recovery following pancreatitis. Additional experimental data from rats suggests that ethanol intake leads to inhibition of plg activation and consequent impairment of the pancreas damage recovery process. Therefore, we hypothesize that ethanol-induced alterations in the plg system are an integral part of the mechanisms underlying fibrogenesis in alcoholic pancreatitis. The specific aims of this proposal are to elucidate the role and regulation of the pancreatic plg system during tissue repair processes and the mechanisms of action of ethanol on this system in mediating pancreas fibrosis. Our approach to accomplish these aims will be to examine the course of cerulein-induced pancreatitis in mice with genetic alterations of plasminogen activator inhibitor-1 (PAI-1), the major physiologic regulator of the plg system. The experimental groups will include PAI-1 deficient mice, transgenic mice overexpressing PAI-1 and their respective wild type controls. The effects of ethanol intake will be evaluated by feeding ethanol-containing diets to these mice. Finally, whether ethanol modulates the operation of the plg system in matrix turnover will be examined in primary cultures of pancreatic stellate cells (PSC), the major ECM-depositing cells in the fibrotic pancreas. The completion of these objectives will provide insights into the participation of the plg system in the maintenance of pancreas architecture and in the pathogenesis associated with alcohol abuse. Therapeutic strategies focusing on the regulation of plg activation may be central in preventing or reverting alcohol-induced pancreas fibrosis. [unreadable] [unreadable] [unreadable]